About one-third of patients who have rheumatoid arthritis (RA) develop symptoms of inflammation outside the synovium, so-called extra-articular manifestations (ExRA), such as pericarditis, pleuritis, interstitial lung disease, Felty's syndrome, scleritis, keratitis, and vasculitis including mononeuritis multiplex as well as vasculitis involvement of internal organs, and the central nervous system. ExRA manifestations have been reported to occur mainly in patients with severe articular disease and are associated with an excess morbidity for disease related and other conditions, and increased mortality. Suggested predictors of ExRA features include genetic, clinical and serologic factors. The highest frequencies of RA-associated HLA-DR molecules are seen in patients with extraarticular RA. This study seeks to identify genetic risk factors predisposing patients who develop ExRA. Special emphasis will be put on the effect of different HLA polymorphisms and allelic combinations on the targeting of RA to different organ systems. The specific aims are to: 1. Expand a DNA bank from patients and ethnically matched controls to create the facility for large scale association studies in RA. The genetic information from the DNA bank will be linked to a database of clinical parameters collected during long-term follow-up of RA patients seen at Mayo Clinic. 2. Evaluate the impact of a series of candidate genes on the clinical phenotype of RA, including HLA class I genes, HLA class II genes and polymorphisms of inflammatory cytokines. 3. Assess the use of phenotypic immunologic markers as predictors of the clinical course of RA including deficiency for CD28, and aberrant expression of CD158 and 161 on T lymphocytes. The long-term goal is to establish profiles of genetic risk determinants associated with different patterns of RA to eventually be used as biomarkers in risk assessment and clinical management. This proposal is meant as the cornerstone for a long-term investigative initiative into the nature of RA, and will provide the resources and foundation for the development of a series of clinician-investigators at the beginning of their careers. The mentorship program proposed in this grant is critical to this long-term goal.